Advanced breast cancer leads to significantly higher mortality because it metastasizes to vital organs. Emerging evidence underpins that epigenetic alterations play critical roles in tumor progression and metastasis. However, there are only limited treatment options for patients with metastatic breast cancer, most with negligible clinical benefits. Thus, it is critical to identify and validate effective drug targets for developing effecive breast cancer therapies. The long-term goal is to elucidate the roles of epigenetic events that drive tumor initiation and progression and to translate these findings to the clinic. The objective of this proposal is to identify the epigenetic regulators that drive breast cancer metastasis and t develop effective strategies to prevent and eliminate breast cancer metastasis. The central hypothesis is that key epigenetic regulators are crucial for breast cancer metastasis and can be targeted for the treatment of metastatic breast cancer. The hypothesis is supported by the strong preliminary data derived from systematic bioinformatic analyses of breast cancer patient samples and functional validation of RBP2 as a driver of breast cancer metastasis. The rationale for the proposed research is that better understanding of epigenetic regulators of tumor metastasis will result in new and innovative approaches to breast cancer treatment. Therefore, the hypothesis will be tested by pursuing the following two specific aims: 1) Determine the requirement of top 4 prioritized epigenetic regulators of breast cancer metastasis, 2) Evaluate the specificity and efficacy of RBP2 and EZH2 as biomarkers and therapeutic targets in metastatic breast cancer. The proposed research is innovative, because of the novel hypothesis that epigenetic regulators are essential for metastasis progression and the systematic approach to integrate sophisticated functional validation assays with bioinformatic screen of patient derived datasets. The proposed research is significant, because it is expected to vertically advance and expand our understanding of epigenetic regulation in metastasis. Such knowledge is critical for the development of cancer therapies targeting epigenetic aberrations.